Flaxseed oil reduces the growth of human breast tumors (MCF‐7) at high levels of circulating estrogen

Flaxseed (FS) has been shown to attenuate mammary tumorigenesis, possibly due to its high α‐linolenic acid (ALA)‐rich oil (FSO) content. This study determined the effect of FSO on the growth of estrogen receptor‐positive human breast tumors (MCF‐7) in ovariectomized athymic mice at high premenopausal‐like estrogen (E2) levels. Mice with established MCF‐7 tumors were fed basal diet (control) or basal diet supplemented with FSO (40 g/kg) for 8 wks. Compared with control, FSO reduced tumor size (33%, p<0.05) and tumor cell proliferation (38%, p<0.05) and increased apoptosis (110%, p<0.001). FSO also reduced human epidermal growth factor receptor‐2 (79%, p<0.05) and epidermal growth factor receptor (57%, p=0.057) expression, which then may have led to a reduction in Akt (54%, p<0.05) and phosphorylation of mitogen‐activated protein kinase (MAPK) to phosphorylated MAPK (pMAPK, 28%, p<0.05). Insulin‐like growth factor‐1 receptor, vascular endothelial growth factor receptor, MAPK and phosphorylated Akt were not affected. FSO increased (p<0.001) serum ALA, eicosapentaenoic acid and docosahexaenoic acid and, in vitro, ALA reduced MCF‐7 cell proliferation (33%, p<0.001). Thus, FSO regressed estrogen receptor‐positive human breast tumorigenesis at high E2 levels via downregulation of the growth factor mediated pathway, likely through its ALA content, and may explain the anti‐tumorigenicity of FS.     

Involvement of ERK,Akt and JNK signalling in H2O2‐induced cell injury and protection by hydroxytyrosol and its metabolite homovanillic alcohol

The olive oil polyphenol, hydroxytyrosol (HT), is believed to be capable of exerting protection against oxidative kidney injury. In this study we have investigated the ability of HT and its O‐methylated metabolite, homovanillic alcohol (HVA) to protect renal cells against oxidative damage induced by hydrogen peroxide. We show that both compounds were capable of inhibiting hydrogen peroxide‐induced kidney cell injury via an ability to interact with both MAP kinase and PI3 kinase signalling pathways, albeit at different concentrations. HT strongly inhibited death and prevented peroxide‐induced increases in ERK1/2 and JNK1/2/3 phosphorylation at 0.3 μM, whilst HVA was effective at 10 μM. At similar concentrations, both compounds also prevented peroxide‐induced reductions in Akt phosphorylation. We suggest that one potential protective effect exerted by olive oil polyphenols against oxidative kidney cell injury may be attributed to the interactions of HT and HVA with these important intracellular signalling pathways.     

Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1

Extra virgin olive oil is rich in phenolic compounds which are believed to exert beneficial effects against many pathological processes, including the development of colon cancer. We show that one of the major polyphenolic constituents of extra virgin olive oil, hydroxytyrosol (HT), exerts strong antiproliferative effects against human colon adenocarcinoma cells via its ability to induce a cell cycle block in G2/M. These antiproliferative effects were preceded by a strong inhibition of extracellular signal‐regulated kinase (ERK)1/2 phosphorylation and a downstream reduction of cyclin D1 expression, rather than by inhibition of p38 activity and cyclooxygenase‐2 (COX‐2) expression. These findings are of particular relevance due to the high colonic concentration of HT compared to the other olive oil polyphenols and may help explain the inverse link between colon cancer and olive oil consumption.     

Quercetin‐induced apoptotic cascade in cancer cells: Antioxidant versus estrogen receptor α‐dependent mechanisms

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti‐proliferative effects in many cancer cell lines. Antioxidant or pro‐oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin‐induced anti‐proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor α (ERα; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H₂O₂‐induced ROS production both in the presence and in the absence of ERα. However, this flavonoid induces the activation of p38/MAPK, leading to the pro‐apoptotic caspase‐3 activation and to the poly(ADP‐ribose) polymerase cleavage only in the presence of ERα. Notably, no down‐regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERα‐dependent mechanism involving caspase‐ and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.     

Differential effects of resveratrol and its naturally occurring methylether analogs on cell cycle and apoptosis in human androgen‐responsive LNCaP cancer cells

Stilbenes are phytoalexins that become activated when plants are stressed. These compounds exist in foods and are widely consumed. Resveratrol is a grape‐derived stilbene, which possesses a wide range of health‐promoting activities, including anticancer properties. Several other stilbenes structurally similar to resveratrol are also available in food, but their biological activities remain largely unknown. In this study, we compared the effects of resveratrol and its natural derivatives pterostilbene, trans‐resveratrol trimethylether, trans‐pinostilbene and trans‐desoxyrhapontigenin on androgen‐responsive human prostate cancer LNCaP cells. We found that these compounds exert differential effects on LNCaP cell growth, cell cycle and apoptosis. Trans‐resveratrol trimethylether appeared to be the most potent compound among the stilbenes tested. Treatment of LNCaP cells with trans‐resveratrol trimethylether resulted in G2/M blockage while other compounds, including resveratrol, induced G1/S arrest. Moreover, different from other compounds, trans‐resveratrol trimethylether induced apoptosis. At the molecular level, the effects of these compounds on cell cycle correlated with induction of the cyclin‐dependent kinase inhibitor 1A and B mRNA levels. Additionally, these compounds also inhibited both androgen‐ as well as estrogen‐mediated pathways. These results provide mechanistic information on how resveratrol and its methylether analogs may act to contribute to potential antiprostate cancer activity.